Phenylbenzofuran acrylic acid compounds and salts and esters thereof

ABSTRACT

Benzofurans and 2,3-dihydrobenzofurans optionally substituted at the 2 position by halogen or lower alkyl, substituted at the 3 position by optionally substituted phenyl, substituted on the benzo ring by a lower alkanoic or acrylic acid group or a salt, ester or amide thereof, optionally substituted on the carbon of said lower alkanoic group bonded to the benzo ring, and optionally substituted on the benzo ring, are active antiinflammatory, anti-pyretic and analgesic agents or are intermediates in the preparation of such agents.

United States Patent Scherrer PHENYLBENZOFURAN ACRYLIC ACID COMPOUNDS AND SALTS AND ESTERS THEREOF Inventor: Robert A. Scherrer, White Bear Lake, Minn.

Riker Laboratories, Inc., Northbridge, Calif.

Filed: Nov. 16, 1971 Appl. No.: 199,318

Assignee:

US. Cl ..260/346.2 R,260/247.2 R,.

References Cited UNITED STATES PATENTS 8/1972 Kaltenbronn et al. 260/3462 R Primary ExaminerRaymond V. Rush Attorney, Agent, or Firm-Alexander, Sell, Steldt & DeLaHunt [57] ABSTRACT Benzofurans and 2,3-dihydrobenzofurans optionally substituted at the 2 position by halogen or lower alkyl, substituted at the 3 position by optionally substituted phenyl, substituted on the benzo ring by a lower alkanoic or acrylic acid group or a salt, estern or amide thereof, optionally substituted on the carbon of said lower alkanoic group bonded to the benzo ring, and optionally substituted on the benzo ring, are active anti-inflammatory, anti-pyretic and analgesic agents or are intermediates in the preparation of such agents.

7 Claims, No Drawings PHENYLBENZOFURAN ACRYLIC ACID COMPOUNDS AND SALTS AND ESTERS THEREOF The present invention relates to benzofurans and 2,3- dihydrobenzofurans optionally substituted at the 2 position by halogen or lower alkyl, substituted at the 3 position by optionally substituted phenyl, substituted on the 5,6 or 7 position of the benzo ring by a lower alkanoic acid group or a salt. ester or amide thereof, optionally substituted on the carbon of said lower alkanoie group bonded to the bcnzo ring. and optionally substituted on the benzo ring.

The compounds of the invention are antiinflammatory agents, or intermediates for the synthesis thereof. Certain benzofuran derivatives containing both phenyl and acetic acid substituents are known to the art. See various publications by J. N. Chatterjea. However, these compounds contain the alkanoic acid substituent on the heterocyclic furan portion of the compound, not the benzo fragment of the benzofuran moiety. In addition, both the 2 and the 3 positions of the furan ring of the compounds of the prior art are interchangeably substituted by the phenyl and acetic acid substituents. The compounds of the art have no known use. In particular they are not known to be active as pharmaceuticals.

It is an object of the invention to provide compounds which are anti-inflammatory agents.

It is an object of the invention to provide compounds which are anti-pyretic agents.

It is an object of the invention to provide compounds which are analgesic agents.

It is a further object of the invention to provide a method for controlling inflammation in mammalian tissue.

It is a further object of the invention to provide a method for controlling fever.

lt is a further object of the invention to provide a method for relieving pain.

It is still another object of the invention to provide anti-inflammatory compositions containing one or more substituted benzofurans and 2,3- dihydrobenzofurans as active ingredients therein.

It is still another object of the invention to provide anti-pyretic compositions containing one or more substituted benzofurans and 2,3-dihydrobenzofurans as active ingredients therein.

It is still another object of the invention to provide analgesic compositions containing one or more substituted benzofurans and 2,3-dihydrobenzofurans as active ingredients therein.

lt is still another object of the invention to provide novel intermediates in the preparation of the antiinflammatory, anti-pyretic and analgesic agents of the invention and processes using the novel intermediates to prepare the active agents.

Still other objects will be made apparent by the following specification.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there is provided a class of compounds of the formula 9 l R R zc(ca -c 3 1 wherein Z is hydroxyl, lower alkoxy,

1 Y 1 1 -NH2, may -NY Y2. O(CH N Y 1 ocH eHcH oH, -oca oca -OCH2OCY R is hydrogen or alkyl containing not more than two carbon atoms; R is hydrogen or, with R, forms =CH R and R are hydrogen or, together, a carbon-carbon bond; R is hydrogen or lower alkyl, provided that when R and R form a bond, R may be halogen;

Y and Y are lower alkyl or, together, form a cyclic.

group Y is lower alkyl, lower alkoxy, halogen, nitro, diloweralkylamino or hydroxyl; Y is lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, nitro, diloweralkylamino, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl or hydroxyl;

m is 23', n is O2; p is O-2 and r is 0-5. Preferably the carbon atom carrying R and R is substituted at the 6 or 7 position of the benzofuran structure.

The invention also includes pharmaceutically acceptable salts of the acid-form compounds (the compounds in which Z is OH). The work lower in the foregoing and elsewhere herein indicated a group containing not more than four carbon atoms.

The acid-form compounds of the invention and the pharmaceutically acceptable salts thereof, are useful as intermediates to prepare the acids. in most cases the esters and amides appear to be converted in vivo to the active acid, and thus they provide pharmaceutical activity of themselves. In addition, the esters and amides have different physical properties, for example solubility. Such a variety of physical properties can be useful to maximize the biological availability of the parent acid by varying the absorption, blood transport, and the like, of the pharmaceutical compounds. In addition, as is known, longer chain fatty acids are degraded in vivo to the lower acid having two less carbon atoms. Thus a 7-benzofuranbutyric acid is considered the metabolic equivalent of the corresponding 7-benzofuranacetic acid in most mammalian species. The corresponding 3-hydroxybutyric acid is the intermediate and hence also is equivalent metabolically to the acetic acid (which has two fewer carbon atoms).

3 4 Preferably, in the compounds of the invention, r is stereomers ofthe free acid may be formed with optical- 2 P tly those compounds wherein ly-active amines, such as quinine, brucine. cinchonidine, cinchonine, hydroxyhydrindamine, menthyla- 9 1 2 mine. morphine, a-phenylethylamine, phenyloxynaph- ZC (CH C thylmethylamine, quinidine, l-fenchylamine, strychnine, basic amino acids such lysine, arginine. amino acid esters and the like. Similarly, ester diastereomers is of the free acid may be formed with optically-active al- 0 cohols, such as borneol, menthol, 2-octanol and the flogcfi like. Especially preferred is the use of cinchonidine to 2 give the readily decomposable diasteromer salt which or may then be resolved by dissolving in a solvent, such as O qH acetone, and distilling the solvent at atmospheric presn 3 sure until crystals begin to appear and further crystalli- HOC CH I zation produced by allowing the mixture to cool to are most preferred. room temperature, thereby separating the two enantio- Additional preferred classes of compounds of the inmorphs. For example, the (d) acid may then be recovvention are those wherein the phenyl substituent on the ered from the (d) salt by extracting the salt between an furan ring is unsubstituted or halo substituted (espeinorganic solvent, such as petroleum ether, and dilute cially by fluorine or chlorine, most preferably fluorine); 2O hydrochloric acid. wherein p is zero; and wherein n is zero or one (most Derivatives of the resolved form of the free acid then preferably wherein n is zero). Preferably also R is hymay be prepared in the usual way. These derivatives d generally are more active than derivatives of racemates ln compounds of the invention, wherein R is hydroof the same compounds. Consequently, the biologically gen and R is not hydrogen, the carbon atom to which active form of these compounds substantially free of R is chemically bonded is an asymmetric carbon the other form, is a still further aspect of this invention. atoms. In this case the compounds of the invention are The active form is generally the ((1) form but absolute generally present in the form ofa racemic mixture. The rotation and even the sign of rotation of the more acresolution of such racemates can be carried out by a tive form can vary with substitution and compounds number of known methods. For example, some racemust be tested in biological assays to establish their relmic mixtures can be precipitated as eutectics instead of ative activity. mixed crystals and can thus be quickly separated and Compounds of the invention wherein R and R toin such cases can sometimes be selectively precipitated. gether form a methylene group (=CH are all useful The more common method of chemical resolution is, intermediates, but some are also biologically active. however, greatly preferred. By this method diastereo- The compounds of the invention are prepared by mers are formed from the racemic mixture by reaction multi-step synthetic sequences. The most convenient ofwith an optically active resolving agent. Thus, an optithese start with substituted phenols and form substically active base can be reacted with the carboxyl tuted benzofuran derivatives. The substituted benzofugroup. The difference in solubility between the diasteran derivatives are then reacted to obtain the aliphatic reomers formed permits the selective crystallization of acid side chain on the benzo ring. Those skilled in the one form and regeneration of the optically-active acid art will recognize that many variations of these sefrom the mixture. There is, however, a third method of quences exist. The following discussion describes some resolving which shows great promise. This method is of the useful processes for obtaining substituted benzoone ofthe other forms ofbiochemical procedures using furan derivatives. The temperatures are given in deselective enzymatic reaction. Thus, the racemic acid grees Centigrade. The definitions of the various moican be subjected to an asymmetric oxidase or decareties, such as W, O, Ar, etc., are uniform unless otherboxylase form, leaving the other form unchanged. Even wise noted. more attractive is the use of a hydrolysase on a deriva- PROCESS A tive of the racemic mixture to form preferentially one This process can be represented as follows:

H O ocHdAr W BrcHc'Ar (1) w 0 Q ..sw x I Q form ofthe acid. Thus, esters or amides ofthe acids can wherein W is bromine, chlorine, iodine or methyl, Q is be subjected to an esterase which will selectively sahydrogen or lower alkyl and Ar is C,,H Y, as inponify one enantiomorph and leave the other unformula I. changed. The reactants in step (I) are generally known to the When the free acid is resolved into (d) and (l) enantiart. Equimolar amounts of the reactants, or an excess omorphs, the anti-inflammatory activity is found toreof the phenol, are reacted in the presence of a base, side virtually completely in one isomer. For a-methylgenerally a weak inorganic base such as an alkali metal 3-phenyl-7-benzofuranacetic acid this is the (d) isomer carbonate. A solvent is used, for example glyme, tetraor isomer. The desired isomer of the free acid may hydrofuran, ethanol, pyridine and the like and an inert be prepared by any one of the preceding described reatmosphere may be used. The reaction is carried out at solving methods, preferably working from the free acid from about 50 to the reflux temperature. The comas the starting material. For example, amide or salt diapound of formula ll is isolated by conventional methods such as extraction or elution chromatography. Compounds [I wherein W is halogen are known.

in step (2) the compounds of formula ll are cyclized by heating in polyphosphoric acid. The known compounds of formula III are easily separated and isolated by dilution of the reaction mixture with water and filtration or extraction.

Rearrangement of Ar from ring position 3 to 2 can occur if care is not taken in the cyclization step when Q H. The structure of the product is verified by the ultraviolet absorption spectrum. 3-Phenyl derivatives have A max about 228 and 254, 6 about 25,000 and 13,000 respectively, while the Z-phenyl derivatives have about 300 with an e of about 30,000. PROCESS B 9 Br-t'iHCAr :00am

Alk herein is lower alkyl. Steps l and (2) are essentially the same as steps (1) and (2) of Process A. The reaction of step (I) uses generally known reactants. The compounds of formula IV are known.

PROCESS C Hal herein is chlorine, bromine or iodine. When this method is used, R and Y may not be halogen, and Ar is not substituted by halogen. In step (1 the benzofuran is reacted with cuprous cyanide in a solvent such as quinoline. Step (2) is the reaction of the nitrile with methyl Grignard reagent. in step (3) the methyl ketone is converted to a carboxylic acid by, for example, the Willgerodt reaction.

PROCESSD w OCH t l oAlk W O (a O LU FE? OAlk -Ar' 7 The reactants of step (I) are known compounds, readily cyelized in base such as sodium ethoxlde m ethanol to the corresponding benzofurans (VI). The compounds of formula VI are isolated by extraction.

In step (2) the hydrolysis of the ester to the acid is carried out under acidic or basic conditions. Alternatively. if W is methyl, hydrolysis is preferably preceded.

by bromination of the methyl group with N- bromosuccinimide under free-radical conditions such ocHc'Ar w W 9 l ooAlx 2) woman s 0 as are known to the art, followed by reaction with an alkali metal cyanide to give cyanomethyl derivative.

Step (3), the decarboxylation, is carried out by any of the well-known methods employed in the art, for example heating in quinoline in the presence of a copper catalyst.

PROCESS E CH-'OAlk 5 oon c'Ar ca soon 2 o Y herein is hydrogen, lower alkyl, lower a1koxy,halogen or dialkylamino. The group 1 R QHCO AlK cannot be ortho to the hydroxy group in the reactants of this process. in step (I) a phenoxyacetophenone ester is formed as previously described in Process A, step (1).

In step (2) the cyclization is carried out as described in Process A, step (2) to give the novel intermediate Vlll. When Y is hydrogen, cyclization may occur at either of the positions ortho to the group OCH- 7 8 CO Alk on the benzo ring, and when these positions S (1 may he a -fled out by any ofthe well-known are non-equivalent, two different isomeric products are h d f r preparing G i d reagents; h d formed. These isomers are separated by conventional furan i a preferred l St (2) may b r i d method- Such as elutleh ehromatography- Vapor Phase out by a standard Grignard reaction with formaldechromatogr phy. fr i n ry z i n, n h 5 hyde, with subsequent acidification to the alcohol. Step like. (3) requires displacement of the hydroxyl by a halide The intermediates of formulae III, IV, V], and Vll all by any f the wdhkhowh methods f the f examcontain the benzofuran nucleus with an aryl substituent pie reaction i h a h d h l id a phosphorus at the 3p05lti0h- These intermediates are used in acid or thionyl halide. or conversion to the mesylate or further Synthetic Sequences wherein the objective is to H) tosylate. The reaction is preferably carried out in an Provide Compounds which also include the radical inert solvent (for example benzene, toluene. xylene and the like) with thionyl chloride at any suitable tempera- Q 3 ture, but especially in benzene at reflux temperature ZC(CH C" until the reaction is substantially complete.

&2 IS The displacement of the halide with a cyanide by any of the well-known methods of the art is the reaction of step (4). Suitable inorganic cyanides, for example sothe heme ring defined herelhahove dium cyanide, potassium cyanide and the like, are re- The compounds of formula are compounds of acted in an inert solvent, such as dimethylsulfoxide, formula I which y be hydrolyzed, under acidic or dimethoxyfuran,acetone,aqueous alcohol and the like. basic Conditions, to Provide other compounds of As an example the reaction is carried out in an acetonem I wherein h radical the q g l5 ethanol-water mixture with potassium cyanide at any suitable temperature, for example at the reflux temperature of the reaction mixture until the reaction is sub- -C'rl-COOH.

i stantlally complete. R In step (5) the reaction is hydrolysis ofthe nitrile by any of the variety of the methods well-known to the art, Furthermore, compounds of formula Vlll may be tranthat is acidic, or basic hydrolysis, preferably basic hysesterified using methods known to the art such as drolysis with an alkali metal hydroxide in ethanol. acidic or basic catalysis. The compounds of formula PROCESS G OH OH I I MgHal CH -CO Alk CH -C-COOH O L @E @L} CH COOH (3) CH ca =c 000a ,0 Oi. O (A) Ar AI Vlll may be converted to carboxylic acid halides by re- In step (1) the Grignard reagent is reacted with an action with the usual reagents such as thionyl chloride alpha keto ester, preferably ethyl pyruvate under any and phosphorus pentachloride. The acyl halides can ofthe well-known Grignard condensation type reaction then be converted to amides, esters. salts or acids. conditions. In step (2) hydrolysis is accomplished by The synthetic sequences whereby benzofuran interany means well-known to the art. Step (3) is carried out mediates are converted to compounds of formula I, by any dehydration procedure well-known in the art. part cularly carboxylic acids, are described further Step (4) is catalytic reduction by methods wellherelnbelow. known to the art such as reduction over a catalyst, for PROCESS r .9 a B! 2:5"35liam palladium on carbon, platinum,

Hal 0 MgHal O CH OH 0 Ar r CH COOH 2 N CH a1 0 0 a51. rea 9L Ar 9 10 Raney nickel, platinum oxide and the like preferably wherein R is methyl or ethyl. under moderate hydrogen pressure (Ste 60 pounds) in In step I the benzofuranacetic ester is converted to an inert solvent such as lower alkanols, aromatic comthe reactive anionic intermediate by the action of a pounds, tetrahydrofuran, acetic acid, dioxane and the strong base such sodamide, sodium hydride, lithium like at any suitable temperature, C. to reflux temper- N,N-dialkylamide and the like. The anionic intermediature of the system, preferably at room temperature ate is used without isolation for step (2). until the reaction is substantially complete. In step (2) alkylation is carried out by reaction with 7 PROCESS H an alkyl halide such as methyl bromide, methyl iodide CH. lifll ill or .3 ,i co Alk 00 Alk 6 O c,,LA K Y O 2 r\\ O 2 (9i ALL O 'i\ i g v I 's/ Ar Ar Ar in step (1) the benzofuran is reacted with a halog e and ethyl bromide in an inert solvent such as benzene, nating agent. Presently preferred is N- diethyl ether, dimethyl sulfoxide and the like at any bromosuccinimide. Free radical conditions which prosuitable temperature from -80 to reflux temperature mote side chain halogenation are required, for example until the reaction is substantially complete. cobalt stearate and tertiary-butyl hydroperoxide may PROCESSJ be used as a catalyst combination, and a strong source CH CN BCHCN of visible light is commonly useful. 2

Step (2), displacement of the halide with a cyanide, O O

Step (3), hydrolysis of the ester, is carried by meth- 40 is carried out as described in step (4), Process (F). l \g ods well known to the art. 1' Ar Step (4), simultaneous hydrolysis of the ester and the 6 nitrile is carried out by vigorous hydrolysis with an alkali metal hydroxide in ethanol.

Step (5), selective decarboxylation, is carried out by O heating in a quinoline-pyridine mixture until about one 42).. a mole of carbon dioxide evolved.

Step (6 decarboxylation, is carried out as described Ar in step (3) Process (D). H Step (7),hydrolysis ofthe nitrile, is carried out by the In step (I) the anionic intermediate is fig 'g as methods described for Step Process described in step (l), Process (l). in step (2), the alky- PROCESS I lation is carried out as described in step (2), Process (1). The hydrolysis of step (3) is carried out as described in step (5), Process (F). CH CO Alk C MK PROCESS K O l M a 1 6 a i a H li) w\- QT O g R HCO Alk K? 1) r A a r Ar R 6 CHCO Alk R -CHCOOH Step l) is a Grignard reaction of a tert butyl alphahaloacetate, alpha-halopropionate or alphahalobutyrate by methods well known to the art. Step (2) is the hydrolysis of the ester under known acidic or basic conditions.

PROCESS L ln this process, R must be hydrogen or alkyl. The reduction is carried out as in Process G, step (4) but requiring a longer time or more vigorous condition. An

example is the use of a catalyst in a lower alkanol such as ethanol as the solvent. The comparable dehydrogenation reaction can also be utilized to form compounds of the invention utilizing known techniques, e.g., heat- Compounds of the invention wherein y" is not hydrogen are prepared by the processes A through N described hereinabove by incorporating the substituents in the starting phenols, or by appropriate reaction of the intermediates as would be apparent to one skilled in the art. Other transformations of one substituent to another on the structure of formula 1, constitute additional processes for the preparations of these compounds. Thus Y,, is transformed to another Y and/or Ar is converted to another Ar and/or R to another R by methods familiar to those skilled in the art. Examples include reactions as halogenation, nitration, reduction ofa nitro group to an amine, alkylation of hydroxy ing in decalin in the presence of palladium on charcoal. groups and amines and oxidation of sulfides to sulfox- PROCESS M CH3 C5 CH Het 1 Ar A Ar CH C OOH In step l the 2 position is halogenated with molecular halogen, preferably in an inert solvent. Chlorine and bromine are the preferred halogens. Step (2) is sidechain halogenation effected as described in step (1).

Process H. Step (3) is carried out as described in step (4), Process F. Step (4) is effected using the methods of step (5), Process F, preferably using acidic conditions.

PROCESS N Hal CH In step l the dialkyl malonate is treated with strong base such as sodium hydride, then reacted with the halomethyl-3-arylbenzofuran, preferably in ethanol. In

step (2) decarboxylation is readily effected by known methods, for example by heating the dry solid reactant to to 200.

ides.

CH CN (3) i Ha 1 M COOH I CH C HCOOH C H O OOH bradykinin induced rat foot edema test, the inhibition of ultraviolet-light-induced erythcma test (guinea pig), the rat adjuvant arthritis assay. the Randall-Selitto assay, the phenylquinone writhing assay for analgetic activity and the like. Leading references to the rat foot edema test are:

3. Winter, Proc. Soc. Exper. Biol. Med. 1112554,

Leading references to the guinea pig erythema test are;'

1. Wilhelmi, Schweiz. Med. Wschr. 792577, 1949,

and

2. Winder, et al., Arch. Int. Pharmacodyn. 116:261,

The compounds of this invention have a high degree of anti-inflammatory activity and are of value in the treatment of arthritic disorders and like conditions which are known to respond to treatment by drugs with anti-inflammatory activity. In addition, the compounds of the invention have a useful degree ofantipyretie and analgesic activity. For these purposes they are normally administered orally in tablets or capsules, the optimum dosage depending upon the particular compound being used and the type and severity of the condition being treated. Although the compounds of the invention are preferably administered orally, they may also be administered parenterally or by suppository.

Compounds of the invention are active in one or more of the standard assays. Preferred compounds are active at dosages of 100 mg./kg. or less in one of the assays listed herein-above, and most preferred compounds have activity equal to or greater than phenylbutazone in one or more of these assays.

The following examples are given for the purpose of further illustrating the procedures ofthe present invention, but are not intended, in any way, to be limiting on the scope thereof. Thus, while the majority of the examples relate to the acid form compounds (in which Z is OH), the other compounds ofthe invention can also be prepared. Also, although the examples relate for the most part to compounds in which the furan ring is unsaturated, it is understood that those compounds in which the fa ran ring is saturated (R" and R are hydrogen) are also contemplated. The melting points are uncorrected. the temperatures are in degrees Centigrade and the pressures in millimeters of mercury.

EXAMPLE 1 Process A, step (1) Phenacyl bromide (475 g., 2.38 mole) is added to a mixture of 2-bromophenol (400 g., 2.3 mole) and potassium carbonate (470 g., 3.46 mole) in glyme (1,600 ml.) under a nitrogen atmosphere and the stirred mixture is heated to reflux temperature and maintained at reflux for 8 hours. Some solid is present. The liquid portion is decanted, then evaporated to dryness. The residue after this evaporation is boiled in benzene and filtered.

The solid pot residue remaining after decanting is extracted with hot benzene several time, and these benzene extracts are combined with the benzene filtrate.

Hexane is added to the cooling benzene and a first crop collected. Partial evaporation gives a second crop. The white solid is a1pha-(2-bromophenoxy)acetophenone, m.p. 1l3.5115 C.

EXAMPLE 2 Process A, step (2 Polyphosphoric acid (4200 g.) and alpha-(2- bromophenoxy)acetophenone from Example 1 (596 g., 2.05 mole) are heated and stirred well at about to C. internal temperature for 4 hours. The reaction mixture is then poured into stirred ice and water (about 8 1. total volume) to give a suspension of white solid. The solid is collected and washed with water, cold dilute sodium hydroxide solution and water until the wash is neutral. The solid is recrystallized from hexane to give white crystals of 7-bromo-3-phenylbenzofuran, m.p. 72-74 C.

7-methy1-3-phenylbenzofuran is obtained by cyclizing the required acetophenone at about 80 C. for 1 to 2 hours. The optimum temperature and times vary with other substituents which may be present.

Additional novel intermediates of this type prepared by the general method of Process A illustrated by Examples 1 and 2 include:

7-bromo-3-(4-fluorophenyl)benzol'uran, m.p.

7-bromo-3-(3-ch1orophenyl)benzofuran, m.p.

7-bromo-3-(4-chl0rophenyl)benzofuran, m.p.

7-bromo-2-methyl-3-phenylbenzofuran, m.p.

7-chloro-3-phenylbenzofuran, m.p. 75.5-76.5 C.

7-bromo-3-(2-chlorophenyl)benzofuran, m.p.

76-80 C. 7-bromo-5-methyl-3-phenylbenzofuran, m .p.

EXAMPLE 3 Process (1, steps 1 and (2) Dried magnesium turnings (46.2 g, 1.92 mole), dry tetrahydrofuran (200 ml.) methyl iodide 1 ml.) and a small portion of7-bromo-3-phenylbenzofuran from Example 2 (total 465.7 g., 1.71 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated the remaining benzofuran (diluted with 1 liter of tetrahydrofuran) is added gradually over 1.5 hours at a rate sufficient to maintain moderate reflux. Heating is continued an additional fifteen minutes, then the mixture is allowed to cool.

Ethyl pyruvate (400 g., 3.45 mole) in dry tetrahydrofuran (3 l.) is cooled to -50 C. and the Grignard mixture is added slowly while maintaining the reaction temperature below 35 C. The mixture is stirred well while allowing it to warm to room temperature over seven hours. The mixture is then heated to its reflux temperature and maintained at reflux for 1 hour. The mixture is evaporated in vacuo to concentrate it to about 1.5 liters. To this concentrate is added concentrated hydrochloric acid (200 ml.) and 1.5 liters of a mixture of ice and water. The organic phase is separated and the aqueous phase is extracted twice with diehloromethane. The organic phase is combined with these extracts and the solution is washed with saturated sodium chloride solution, then dried and concentrated by evaporation in vacuo to about one liter of an oil which is chiefly ethyl 2-hydroxy 2-[7-(3-phenylbenzofuran)Lpropionate.

This oil is dissolved in three liters of95 percent ethanol and 200 ml. of water and the mixture is heated to its reflux temperature. A solution of potassium hydrox ide (232 g.) in water (400 ml.) is added over about one hour. The mixture is maintained at its reflux temperature for 3.5 hours. The mixture is then concentrated to about one-half of its volume and the residue is poured into cold water 1.5 l). The cloudy mixture is extracted with diethyl ether (700 ml. portions).

The aqueous phase is poured into excess dilute hydrochloric acid and the mixture is cooled and acidified with hydrochloric acid. The solid is collected by filtration and washed with several portions of hot water, then with petroleum ether. The white solid is 2- hydroxy-2-[7-(3-phenylbenzofuran)lpropionic acid, m.p. l12.5l 17 C.

Another novel compound of the invention prepared by the general method illustrated by Example 3 is 2- hydroxy-2-{7-l 3-( Z-methylphenyl )benzofuran ]}propionic acid, m.p. 166166.5 C. In general the hydroxy acid may be used directly as obtained for the next step.

EXAMPLE 4 Process G, step (3) Dry 2-hydroxy2-[ 7-( 3phenylbenzofuran lpropionic acid (337 g., 1.19 mole) in toluene (3 1) under a nitrogen atmosphere is treated with para-toluencsulfonic acid hydrate (70 g.) and hydroquinone (l g.) while refluxing to azeotropically remove water in a Dean-Stark trap. After refluxing for three hours the reaction mixture is cooled, diluted with hexane and cooled by an ice bath. The solid product is collected by filtration washed with petroleum ether, then aqueous ethanol to give 2-[7-(3-phenylbenzofuran)lacrylic acid, m.p. 195.5198.5 C.

Additional novel compounds of the invention prepared by the general method illustrated in Example 4 include:

2-[ 7-( 2-methyl-3-phenylbenzofuran ]acrylic m.p. ism-181 C.

2- {7-1 3-( 2-chlorophenyl)benzofuran]}acrylic acid,

m.p. l89l9() C.

2 {7-[3-(3-chlorophenyl)benzofuran]}acrylic acid,

an oil 2- 7-[3-(4-fluorophenyl)benzofuran]}acrylic acid.

EXAMPLE 5 Process (1, step (4) acid,

Z-l7-(3-Phenylbenzofuran)lacrylic acid (40 g., 0.15 mole) is dissolved in warm ethanol (750 ml.) and palladium on charcoal (3 g.) is added. The reduction is carried out using hydrogen gas at 40 psi. initial pressure. The mixture is filtered. then evaporated in vacuo to dryness. The residue is dissolved in benzene (225 ml.) diluted with hexane and cooled. The solid is collected by filtration and again recrystallized from a hexane benzene mixture. The white crystal obtained are 2-[7- (3-phenylbenzofuran)lpropionic acid, m.p. l67.5l68.5 C.

Analysis: /IC 71 H Calculated for C H O 76.7 5.3 Found: 77.1 5.3

Additional novel compounds of the invention pre' pared by the general method illustrated by Example 5 include.

2-[7-(2-methyl-3-phenylbenzofuran ]propionic acid.

m.p. 146-l47 C. 2-{7-[3-(4-chlorophenyl)benzofuran]}propionic acid, m.p. -l4l C. 2- {7-[ 3-( 3-ch1orophenyl )benzofuran ]}propionic acid, m.p. l50l5l C. 2-{7-[3-(4-fluorophenyl)benzofuran]}propionic acid, m.p. 169.5-17l.5 C. 2-{7-[3-(2-chlorophenyl)benzofuran]}propionic acid, m.p. l89190.5 C.

EXAMPLE 6 Process F, steps (1) and (2) Dried magnesium turnings (12.2 g., 0.5 mole), dry tetrahydrofuran (50 ml.), methyl iodide (0.5 ml.) and a small sample of 7-bromo-3-(4-fluorophenyl)benzofuran (total 134 g., 0.46 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated an additional 500 ml. of tetrahydrofuran is added, then the remaining benzofuran dissolved in tetrahydrofuran (500 ml.) is added over 1 hour at a rate sufficient to maintain a gentle reflux. The mixture is heated for an additional hour, then heating is stopped.

Paraformaldehyde (41.4 g., 1.38 mole) (dried over phosphorus pentoxide), is depolymerized at about C. while passing the formaldehyde vapor into and over the stirred Grignard reaction mixture. The reaction is exothermic, causing a gentle reflux. When reaction is complete, the mixture is concentrated to about onethird ofits volume, then poured onto ice and water. Diethyl ether (50 ml.) is added, followed by slow addition of concentrated, cold 6N hydrochloric acid (250 ml.). The mixture is extracted with diethyl ether, the extracts are washed with water and saturated sodium chloride solution, dried and evaporated in vacuo to give an oil. The oil is dissolved in absolute ethanol (120 ml.) and concentrated hydrochloric acid (6 ml.) is added. The mixture is heated to reflux temperature and maintained at reflux for 2.5 hours. The mixture is evaporated in vacuo, then the residue is dissolved in diethyl ether, the solution is washed with water and saturated sodium chloride solution, dried and then concentrated to tan oil crude, 3-(4-fluorophenyl)-7-(hydroxymethyl)benzofuran. Pure product has m.p. 8889 C.

An additional novel intermediate compound of the invention prepared by the general method illustrated by Example 6 is:

7-hydroxymethyl-3phenylbenzofuran, m.p. 76-77 C. which can be obtained from either 7-bromo-3- phenylbenzofuran or 7-chloro-3-phenylbcnzofuran. The crude intermediates can advantageously be used directly in the subsequent steps.

EXAMPLE 7 Process F, step (3) 3-(4-Fluorophenyl)-7-( hydroxymethyl)benzofuran (110 g., 0.45 mole) is dissolved in benzene (225 ml.) and added dropwise to refluxing thionyl chloride l ml.). Heating is continued until gas evolution is complete. Excess thionyl chloride and benzene are removed in vacuo, using additional benzene to aid in removing the thionyl chloride. The residue is a brown oil, 7-chloromethyl-3-(4-fluorophenyl)-benzofuran. (500 ml.) is added a solution of sodium cyanide (39.5 g., 0.50 mole) in water 150 ml.). The mixture is heated to its reflux for five hours. The mixture is then evaporated in vacuo to concentrate it. The residue is dissolved in dichloromethane, then washed thoroughly with water, dried and concentratedby evaporation in vacuo. The oily residue is recrystallized twice from cyclohexane, then deposited on 70 g. of a magnesium silicate material used for elution chromatography and chromatographed on 400 g. of the silicate type column. Elution with hexane, benzene-hexane (1:4), (1:1

EXAMPLE 8 Process F, step (4) To a solution of 7'chloromethyl-3-(4fluoropheny1)- benzofuran (130.3 g., 0.50 mole) in acetone (750 ml.) and ethanol J and (3:2), followed by benzene gives the desired product, 7-cyanomethyl-3-(4-fluorophenyl)- benzofuran, in the benzene fractions.

Additional novel intermediate compounds of the invention prepared according to the general method illustrated by Example 8 include:

7-cyanomethyl-3-phenylbenzofuran, m.p. 110-111 C. 7-cyanomethyl-3-(4-chlorophenyl)benzofuran, m.p.

EXAMPLE 9 Process F, step (5) Potassium hydroxide (85 percent, 49 g.), 7- cyanomethyl-3-(4-fluorophenyl)benzofuran (48.8 g., 0.194 mole) and 95 percent ethanol (500 ml.) are mixed and heated at reflux temperature overnight under a nitrogen atmosphere. The mixture is then concentrated by evaporation in vacuo, diluted with water and extracted with diethyl ether. The aqueous phase is filtered, then acidified by the slow addition of hydrochloric acid. The solid is collected by filtration and recrystallized from aqueous ethanol (65 percent) with treatment with decolorizing charcoal, giving yellow crystals. Another recrystallization from an ethanolpetroleum ether mixture (about 5:1) gives yellow crystals of 3-(4-fluorophenyl)-7-benzofuranacetic acid, m.p. l69-170 C.

Analysis: /r/C 7/ H Calculated for C ,,H,,FO,,: 71.1 4.1 Found: 71.0 3.8

1s 3-phenyl-6-benzofuranacetic acid, m.p. l43-l44 C.

169-170.5 C. The 5 and 6-acetic acids were prepared by way of the esters, Process E.

EXAMPLE 10 Process L 3-Phenyl-7-benzofuranacetic acid (2.5 g., 0.01 mole) is reduced with hydrogen gas using palladium 0n charcoal as catalyst and ethanol as solvent in a Brown hydrogenator. After the absorption of hydrogen stops, the reaction mixture is filtered, then the filtrate is evaporated in vacuo to a white solid. Recrystallization from a benzene-hexane mixture gives white crystals of 2,3-

dihydro-3-phenyl-7-benzofuranacetic acid, m.p. 110.5111.5 C.

Analysis: (C A H Calculated for CMHHO, 75.6 5.55

Found: 75.7 5.6

EXAMPLE 1 l 2-[7-(3-Phenylbenzofuran)]propionic acid (2.85 g., 0.107 mole) is dissolved in hot chloroform and added to a solution of cinchonine (1.74 g., 0.0059 mole) in chloroform. The clear solution is then concentrated on a steam bath under a stream of nitrogen. Acetone and a little diethyl ether (total about 40 ml.) are added. The solution is cooled and the precipitate is collected (1.7 g., m.p. 141-146.5 C.). This precipitate is dissolved in a minimum amount (about 45 ml.) of boiling acetone. The total volume is reduced to 35 ml. and the solution is allowed to stand overnight, then cooled. The solid is collected, 1.44 g., m.p. 148.5149 C. Another recrystallization from acetone gives 1.24 g. of white crystals, m.p. 149-151 C., specific rotation 46 in chloroform. Another recrystallization from acetone gives 1.03 g., m.p. 15l.5152.5 C., specific rotation 41.5. The free acid is now obtained by stirring with dilute hydrochloric acid in diethyl ether, 0.50 g., m.p. 158.5-161 C., specific rotation +58". After recrystallization from a benzene-n-hexane mixture (6 ml:2 ml), (+)2-[7-(3 -phenylbenzofuran)lpropionic acid, 0.40 g., m.p. l57l62 C., a],, "=+58 (chloroform) is obtained.

EXAM PLE 12 Process N Diethyl malonate (12.7 g., 0.079 mole) is dissolved in ethanol (40 ml.) and treated with sodium hydride (0.079 mole). 7-Chloromethyl-3-phenylbcnzofuran (10.0 g., 0.0396 mole) is added and the mixture is heated to its reflux temperature and maintained at reflux for ten hours. Equal volumes of water and diethyl ether are added and the ether extracts are evaporated in vacuo. The residue is dissolved in ethanol and potassium hydroxide (16 g.) is added and the mixture is heated on a steam bath. A yellow solid forms rapidly, but heating is continued overnight. The solution is concentrated by evaporation in vacuo, then equal volumes of water and diethyl ether are added. The ether layer is washed with water, dried, then evaporated to dryness. The residue is recrystallized from benzene to give 3-phenyl-7-benzofuranmethylmalonic acid, m.p. l79-l 80 C.

3-Phenyl-7-benzofuranylmethylmalonic acid (1.8 g.) is heated to 180 C. dry, with an oil bath. Gas is evolved for about 10 minutes. The residue is recrystallized from a mixture of benzene-methanol to give 3-[7-(3- 2-{7-[3-(2-chlorophenyl)benzofuran]}propionic acid is dissolved in methanol and treated with an equimolar amount of sodium hydroxide. After stirring at ambient temperature for 2 hours the reaction mixture is evaporated in vacuo to dryness to give sodium 2-{7- [3-(2-chlorophenyl)benzofuran] propionate, m.p. 22923 l C.

Analysis: /1 C '/r H Calculated for C,,-,H,,ClNa()- (10.0 3.7 Found: 60.2 4. l

Other salts can be obtained by substituting inorganic or organic bases for the sodium hydroxide, for example calcium hydroxide, aluminum hydroxide, triethylamine and diethanolamine. The choline salt is prepared, e.g., by mixing equivalent weights of a sodium benzofuranacetate and choline choride in ethanol; it can be isolated by filtering off the sodium chloride formed and either concentrating the solution to dryness or precipitating the salt with acetone or hexane.

EXAMPLE 14 Process M, step (1) and (2) 7-Methyl-3-phenylbenzofuran is treated with an equimolar amount of bromine in carbon tetrachloride at room temperature until decolorized. The mixture is concentrated to dryness to remove hydrobromic acid and redissolved in carbon tetrachloride. To this solution is added an equimolar amount of N- bromosuccinimide and catalytic amounts (about one gram/mole of benzofuran) of cobalt stearate and tertiary-butyl hydroperoxide. The mixture is heated to reflux temperature and maintained at reflux for 2 hours while shining a bright floodlight directly upon the reaction mixture. The mixture is cooled, filtered to remove succinimide and concentrated in vacuo to a thick oil which slowly crystallizes on cooling to give 2-bromo-7- bromomethyl-3-phenylbenzot'uran, m.p. l35-l38 C.

EXAMPLE 15 Process M, steps (3) and (4) A solution oi- 2-bromo-7-bromomethyl-3- phenylbenzofuran (35.6 g., 0.092 mole) dissolved in a minimum amount of dimethyl sulfoxide is added to a solution of sodium cyanide (5.9 g., 0.12 mole) in dimethyl sulfoxide (50 ml.) and the mixture is heated at 50 to 60 C. for 2 hours. The dark solution is then poured over ice and the solid precipitate is collected by filtration. The product is 2-bromo-7-cyanomethyl-3- phenylbenzofuran.

To a mixture of 50 percent sodium hydroxide solution (35 ml.) and ethanol (100 ml.) is added Z-bromo- 7-cyanomethyl-3-phenylbenzofuran (10 g., 0.032 mole). The mixture is heated to reflux temperature and maintained at reflux for about 16 hours, then concentrated in vacuo. The residue is diluted with water, then extracted (washed) with diethyl ether. The aqueous layer is acidified with hydrochloric acid, yielding a precipitate which is collected by filtration and recrystallized twice from benzene-hexane mixtures to give 2- y)acetophenone in 5 times its weight of polyphosphoric acid at for 30 minutes. Distillation oi the crude product gives the desired ester, b.p. ca. l90/0.0l mm, m.p. 4345 C.

Heating 27 g. of ester overnight in 250 ml. of ethanol with 50 ml. of 50 percent sodium hydroxide gives 3-phenyl-5-benzofuranacetic acid, m.p. l3 1 .5] 32 C. (after recrystallization from aqueous ethanol).

The required aryloxyacetophenone used as starting material is prepared according to the procedure in Example 1.

By the above sequence and starting with methyl phydroxyphenyl propionate there is obtained 3-phenyl- 5-benzofuranpropionic acid, m.p. 99.5-l00 C.

EXAMPLE 17 A solution of 40 g., of 3-phenyl-7-benzofuranacetic acid in 400 ml. of ethanol and 40 ml. of sulfuric acid is heated under reflux for 4 hours. The solution is partially concentrated under reduced pressure, poured onto ice and extracted with ether. The ether is washed, dried and concentrated and the residue distilled to give ethyl 3-phenyl-7-benzofuranacetate, b.p. 187l89/0.l2 mm.

Analysis: '/r /1 H Calculated for CWHMOH: 77.] 5.7 iund: 77.0 5.8

In a similar manner ethyl 2-[7-( 3-phenyllbenzofuranyl]propionate is obtained from the corresponding acid.

Methyl 3-phenyl-7-benzofuranacetate is obtained as above using methanol in place of ethanol or by heating the potassium salt of 3-phenyl-7-benzofuranacetic acid with excess methyl iodide in dimethylformamide at 5060 C. for 30 minutes.

EXAMPLE 18 A solution of ethyl 3-phenyl-7-benzofuranacetate, 2.0 g., and hydrazine, l g., in ml. of ethanol is heated overnight at reflux. The mixture is cooled and the white precipitate collected. Recrystallization from benzene benzofuranacetate, 2.6 g. of hydroxylamine hydrochloride and 6.3 g. of sodium methoxide in 55 ml. of methano] is heated overnight at reflux. Water and dilute hydrochloric acid are added. The precipitate which forms is collected and recrystallized from ethanol to give 3- phenyl-7-benzofuranacethydroxamic acid, m.p. 163 (dec).

Analysis: /1 C AH /1 N Calculated for c H No z 71.9 4.9 5.2 Found: 71.6 5.1 5.2

EXAM PLE 2U 3-Phenyl-7-benzofuranacetamide is obtained by reaction of the acid chloride (from the acid and thionyl chloride in benzene) with ammonia in ethanol. It has m.p. 163-l 64.5 C, when recrystallized from ethanolwater.

EXAMPLE 2l Z-Dimethylaminoethyl 2-l7-(3-phenylbenzofuranllpropionate is obtained by heating 5.0 g. of the propionic acid with 2.7 g. of Z-chloroethyldimethylamine hydrochloride and 3.9 g. of triethylamine in 25 ml. oldimethylformamide for 24 hours. The product is isolated by dilution with 50 ml. of ether, filtration to remove triethylamine hydrochloride. and extraction into 5 percent hydrochloric acid. from which it is freed with sodium carbonate. The ester is an oil. It can be purified as the hydrochloride, m.p. l86-l87 after recrystallization from isopropanol.

Analysis: /1(' '/i H ,i N

Calculated for C. .,H NO;, HCI: 67.5 (1.5 3.7 Found: 676 6.6 3.8

EXAMPLE 22 3-Phenyl-7-benzofuranacetic acid, 6.0 g., is heated for fifteen minutes with 3.4 g. of sulfuryl chloride in 50 ml. of benzene then left at room temperature overnight to give 2-chloro-3-phenyl-7-benzofuranacetic acid which precipitates from the reaction mixture. Recrystallization from benzene-hexane gives material of m.p. l5().5l52 C.

Analysis: '/1 C A H Calculated for C H ClO 67.l 3.) Found: 673 3.8

EXAMPLE 23 Starting with Z-bromophenol and alpha-bromo-3,4- dichloroacetophenone and using Process A as described in Examples 1 and 2, the compound 7-bromo- 3-(3,4-dichlorophenyl)-benzofuran is prepared. Using Process F as described in Examples 6 to 9, this compound is converted to 3-(3,4-dichlorophenyl)-7- benzoi'uranacetic acid. m.p. l58.5l60 C.

EXAMPLE 24 A solution of 1.0 g. oi 5-methoxy-3-phenyl-7' benzofuranacetic acid in 5 ml. of acetic acid and 1 ml. of 47 percent hydriodic acid is heated at reflux for 16 hours to obtain the corresponding S-hydroxy acid. It is isolated by precipitation with water, extraction into ether and then into sodium bicarbonate solution. Recrystallization from benzene gives 5-hydroxy-3-phenyl- 7-benzofuranacetic acid, m.p. l97.5-l99 C.

Analysis: '/1 C '/1 H Calculated for il 0. 7 l .6 4.5 Found: 7].] 4.6

EXAMPLE 25 Methyl 2-[7-(3-phenylbenzofuran)lpropionate is obtained from methyl 2-[7-(2,3-dihydro-3-phenylbenzofuran)]propionate by heating 20 g. ofthe latter in 50 ml. of decalin with 5 g. of 5% Pd/C for 24 hours. The ester can be purified by distillation or hydrolyzed as illustrated above to 2-l7-(3-phenylbenzol'uran)lpropionic acid.

EXAMPLE 26 As an illustration of an acid hydrolysis of nitrile intermediates a mixture of 5 g. of 3-phenyl-7- benzofuranacetonitrile in 30 ml. of acetic acid, 20 ml.

23 of water and ml. of sulfuric acid is stirred and heated at reflux overnight. On cooling and diluting with water one obtains 3-phenyl-7-benzofuranacetic acid, purified by crystallization from benzene-hexane.

EXAMPLE 27 Process J, steps l (2) and (3) EXAMPLE 28 2-[7-(3-phenylbenzofuran)lacrylic acid can also be reduced with sodium borohydride to the corresponding propionic acid. Five grams of the acrylic acid methyl ester is stirred at room temperature into 60 ml. of ethanol with 0.68 g. of sodium borohydride for 6 hours. The mix is diluted with water and diluted hydrochloric acid and extracted with ether. The ester is hydrolyzed in ethanol-aqueous sodium hydroxide to obtain 2-[7-(3- phenylbenzofuran)]propionic acid.

EXAMPLE 29 By the procedure illustrated in Examples l-2 and 6-9 and starting with a-bromo-4-methylthioacetophenone,

a-bromo-4-methylsulfinylacetophenone, a-bromo-4 methylsulfonylacetophenone, a-bromo-3- trifluoromethylacetophenone and a-bromo-4- dimethylaminoacetophenone respectively, one obtains:

3-(4-methylthiophenyl)-7-benzofuranacetic acid 3-(4-methylsulfinylphenyl)-7-benzofuranacetic acid 3-(4-methylsulfonylphenyll-7-benzofuranacetic acid 3-( 3-trifluoromethylphenyl )-7-benz0furanacetic acid 3-( 4-dimethylaminophenyl )-7-benzofuranacetic acid.

EXAMPLE 30 The following amides of the invention are prepared from the acid chloride of Example 20 by reaction with an amine as in Example 20.

' bromomethyl-5-nitro-3-phenylbenzofuran EXAMPLE 31 2-Methyl-4-nitrophenol is converted to 7-methyl-5- nitro-3-phenylbenzofuran by the method of Process A (Examples 1 and 2). This intermediate is brominated with N-bromo-succinimide, providing 2-bromo-7- which is converted by Process F. steps 4 and 5 to 2-bromo-5- nitro-3-phenyl-7-benzofuranacetic acid.

EXAMPLE 32 Using Processes A and F and starting with Z-bromo- 4-(N,N-dimethylaminophenol and phenacyl bromide one obtains 5-(N,N-dimethylamino)-3-phenyl-7- benzofuranacetic acid.

EXAMPLE 33 3-(4-methoxyphenyl)-7-benzofuranacetic acid is acetic acid is heated at reflux with 47 percent hydroiodic acid overnight to provide 3-(4-hydroxyphenyl)-7- benzofuranacetic acid.

EXAMPLE 34 Using the methods of Examples 1 and 2 and 6 to 9 and starting with a-bromo-4-trifluoromethoxyacetophenone one obtains 3-( 4- trifluoromethoxyphenyl)-7-benzofuranacetic acid.

EXAMPLE 35 Using Process M as illustrated in Examples 14 to 16, 7-methyl-3-(4-nitrophenylbenz0furan (prepared according to Process A) is converted to 2-bromo-3-(4- nitrophenyl)-7-benzofuranacetic acid.

EXAMPLE 36 Using Processes A and F as illustrated in Examples 1 and 2 and 6 to 9 and starting with 2-bromo-4- fluorophenol and phenacyl bromide one obtains 5- fluoro-3-phenyl-7-benzofuranacetic acid.

EXAMPLE 37 The glyceryl ester of 3-phenyl-7-benzofuranacetic acid is prepared by the method described in US. Pat. No. 3,478,040, i.e., reacting the acid with chloroacetonitrile in the presence of triethylamine, heating the nitrile with 2,2-dimethyl-l ,3-dioxolane-3-methanol in the presence of potassium carbonate and hydrolysis of the isopropylidenedioxypropyl ester.

EXAMPLE 3s The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethoxymethane in dimethylformamide to provide methoxymethyl 3-phenyl-7- benzofuranacetate.

EXAMPLE 39 The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethyl acetate is dimethylformamide to provide acetoxymethyl 3-phenyl-7- benzoi'uranacetate.

EXAMPLE 40 By the procedures illustrated in Examples 1 and 2 and 6 to 9, and starting with alpha-bromoacetophenone and 2-bromo-4-t-butylphenol one obtains 5-t-butyl-3- phenyl-7-benzofuranacetic acid, m.p. l40.5l43 C.

What is claimed is:

l. A compound of the formula O ICI wherein Z is hydroxyl or lower alkoxy; R" and R are hydrogen or together, a carbon-carbon bond; R is hydrogen or lower alkyl, provided that when R and R form a bond, R may be halogen; Y is halogen; and r is 01 and pharmaceutically acceptable salts of the acid compounds.

2. A compound of the formula 0 OH I! H 2 O 5 HOG-C l R wherein R is hydrogen, lower alkyl or halogen; Y is UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,862,13M DATED January El, l975 0 (5) Robert A. Scherrer- It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Assignee: "Northbridge" should be --Northridge-- In the Eth line of the abstract: estern" should be --ester- Column 3, line 27: "atoms" should be -atom-- Column 12, line 1: "y "'should be "YD-- Column 25, line 9: The second occurrence of "is" should be The passage at Column 17, lines 7--l8z "(500 ml.) is added.

hexane (lit), (l:l" is misplaced. It should be inserted following "ethanol" at Column 17, line E L Signed and Sealed this sixteenth Day of March 1976 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN Arresting Offic Commissioner ofParenrs and Trademarks 

2. A compound of the formula
 3. A compound according to claim 1 wherein Z is hydroxyl.
 4. A compound according to claim 1 wherein r is zero.
 5. A compound according to claim 1 in which R3 and R4 together form a carbon-carbon bond.
 6. A compound according to claim 2 in which R5 is hydrogen.
 7. The compound 2-(7-(2-methyl-3-phenylbenzofuran))acrylic acid. 